CD44-Targeting for Antitumor Drug Delivery: A New SN-38-Hyaluronan Bioconjugate for Locoregional Treatment of Peritoneal Carcinomatosis
[ Vol. 11 , Issue. 5 ]
A. Serafino, M. Zonfrillo, F. Andreola, R. Psaila, L. Mercuri, N. Moroni, D. Renier, M. Campisi, C. Secchieri and P. PierimarchiPages 572-585 (14)
An innovative approach for cancer therapy implies the use of drugs covalently conjugated to macromolecular carriers that specifically target molecules over-expressed on tumor cells. This drug delivery strategy may allow a controlled release of the drug and a high targeting selectivity on tumor cells, increasing drug cytotoxicity and decreasing its undesirable side effects. We provide in vitro and in vivo preclinical data on the antitumor efficacy of ONCOFID™-S, a new bioconjugate of hyaluronic acid (HA) with SN-38 (the CPT11 active metabolite), that support the validity of the drug delivery strategy implying the use of HA as macromolecular carrier of antineoplastic drugs, an approach based on the over-expression of its target CD44 (the receptor for HA-mediated motility) in a wide variety of cancers. We show that ONCOFID™-S exerts a strong in vitro anti-proliferative activity on CD44 over-expressing rat DHD/K12/trb colon adenocarcinoma cells, as well as on gastric, breast, oesophageal, ovarian and lung human cancer cells, higher than that exerted by unconjugated SN-38. We also demonstrated the in vivo anti-tumor efficacy of locoregional treatment with ONCOFID™-S on two pre-clinical models of colorectal cancer (CRC) in BDIX rats: a) syngeneic model of subcutaneous tumor; b) syngeneic model of metastatic tumor induced by injection of cells into the peritoneal cavity, mimicking the clinical situation of peritoneal carcinomatosis. Specifically, in the latter model ONCOFID™-S is able to dramatically reduce all parameters indicative of a poor prognosis in peritoneal metastatization of CRC without any myelotoxicity or mesothelial inflammation. We propose this CD44-targeted therapeutic strategy for locoregional treatment of peritoneal carcinomatosis from CRC, against which systemic chemotherapy results almost inefficient.
CD44, colorectal cancer, drug delivery, hyaluronic acid, locoregional treatment, peritoneal carcinomatosis, target therapy, confocal laser scanning microscopy, camptothecin, 7-ethyl-10-hydroxy-camptothecin, 7-ethyl-10-[4-(l-piperidino)-lpiperidino] carbonyloxy-camptothecin or Irinotecan
Institute of Translational Pharmacology, CNR, Via Fosso del Cavaliere 100, 00133, Rome, Italy.
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